title: [Significance and creation of novel cyclooxygenase-1 (COX-1) selective inhibitors].
abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to relieve physical and mental pain, and to improve patients' quality of life. However, stomach irritation is a major side effect. Most NSAIDs inhibit cyclooxygenases (COXs), and inhibition of COX-1 on the stomach mucous membrane is thought to be responsible for the gastric disturb- ance. Consequently, development efforts have focused on COX-2-selective inhibitors, while COX-1-selective inhibitors have been rather neglected. Subsequently, however, it was shown that inhibition of either COX-1 or COX-2 alone does not induce gastric damage. Therefore, we have developed the COX-1-selective inhibitor N-(4-aminophenyl)-4-trifluoromethylbenzamide (TFAP), which shows analgesic activity without causing gastric damage. However, metabolism of TFAP generates a colored metabolite, resulting in red-purple coloration of urine after administration. In addition, the analgesic activity of TFAP is weaker than that of indomethacin. Thus, we designed a series of new COX-1-selective inhibitors, the 5-amino-2-ethoxy-N-(substituted)benzamide (ABEX) series, in order to avoid formation of the colored metabolite by modifying the diaminopyridine skeleton. As a result of structural modification and in vitro and in vivo testing of compounds in the ABEX series, we found a novel COX-1-selective inhibitor, 5-amino-2-ethoxy-N-(3-trifluoromethylphenyl)benzamide (ABEX-3TF), which shows better analgesic activity than indomethacin, and does not cause coloration of urine.
authors.affiliation: Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Fukai
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Zheng
authors.forename: Kazunori
authors.initials: K
authors.lastname: Motoshima
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kakuta
mesh_terms: D000631:Aminopyridines / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology; D000700:Analgesics; D001549:Benzamides / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology; D051545:Cyclooxygenase 1; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology; D015195:Drug Design; D005753:Gastric Mucosa / Q000187:drug effects; D006801:Humans
chemical_list: C559679:5-amino-2-ethoxy-N-(3-trifluoromethylphenyl)benzamide; D000631:Aminopyridines; D000700:Analgesics; D001549:Benzamides; D016861:Cyclooxygenase Inhibitors; C550711:N-(5-amino-2-pyridinyl)-4-trifluoromethylbenzamide; D051545:Cyclooxygenase 1